Modulation of HIV-specific CD8+ T and B cell function by CD4+ T helper responses

描述(由申请人提供)：估计每天有6800名新的艾滋病毒-1感染者，这极大地突显了对艾滋病毒-1疫苗开发的迫切需求。尽管我们对HIV-1感染中的体液和细胞免疫反应的理解有了很大的进步，但保护的相关性仍然没有被确定。最近默克疫苗试验的失败，以及使用ALVAC-HIV(VCP1521)与AIDSVAX B/E的Prime Boost组合的RV144 HIV疫苗试验出人意料的适度成功，这些都挑战了我们关于什么是保护性疫苗的概念。引人注目的是，该疫苗不仅诱导了强烈的抗体反应，而且还诱导了强大的HIV-1特异性CD4+T细胞反应。到目前为止，诱导HIV-1特异性CD4+T细胞反应的方法一直受到怀疑，因为这些尝试可能会扩大HIV-1特异性CD4+T细胞靶点的池。然而，在淋巴脉络膜脑膜炎病毒(LCMV)小鼠模型中引人注目的研究表明，病毒特异性白介素21(IL21)分泌的CD4+T细胞反应是建立有效和持久的病毒特异性免疫的关键因素。缺乏IL21或IL21受体(IL21R)的小鼠更容易发生慢性LCMV感染。研究表明，IL21+CD4+T细胞反应可增强病毒特异性CD8+T细胞的细胞毒作用，并直接导致B细胞抗体类型的转换和活化。因此，IL21+CD4+T细胞反应在病毒特异性免疫的协调中起着核心作用。令人惊讶的是，人们对IL21+CD4+T细胞在人类病毒感染中的作用知之甚少。我们的初步数据表明，在HIV-1精英控制者中存在强大的HIV-1特异性IL21+CD4+T细胞反应，其优先靶向是Gag蛋白中的表位。相比之下，在慢性进行性HIV-1感染的受试者中，几乎没有检测到IL21+CD4+T细胞反应。此外，我们有证据表明，IL21信号可以将非控制性CD8+T细胞反应转化为具有很强抑制活性的CD8+T细胞反应。因此，我们的初步数据表明，IL21+CD4+T细胞反应可能是产生有效的CD8+T细胞或B细胞疫苗的关键因素。具体地说，我们建议：1)确定HIV-1特异性IL21+CD4+T细胞的存在和特异性，以及它们在控制病毒复制中的作用。2)确定初次HIV-1感染的早期抗逆转录病毒治疗是否保留了这些特殊反应。3.)评估HIV-1特异性IL21+CD4+T反应如何调节HIV-1特异性CD8+T细胞，并增强其抑制病毒复制的能力。4.)研究以CD4为靶向的治疗性疫苗接种是否能引起这种反应，并最终得出结论。评估IL21+CD4+T细胞如何调节HIV-1特异性B细胞功能。这一建议的基本假设是，HIV-1特异性IL21+CD4+T细胞通过调节HIV-1特异性B细胞功能和增加HIV-1特异性CD8+T细胞的抑制活性，在控制病毒复制方面发挥关键作用。在预防性或治疗性疫苗中诱导和传播这些反应对于长期有效的病毒特异性免疫至关重要。 公共卫生相关性：全世界有3300万艾滋病毒-1感染者，迫切需要一种艾滋病毒-1疫苗。最近默克疫苗试验的失败，以及由两种候选疫苗(ALVAC/AIDSVAX；“泰国试验”)组合而成的疫苗出人意料地取得了不大的成功，这极大地表明了我们对如何开发有效疫苗的理解不足。引人注目的是，所使用的疫苗不仅诱导了抗体，而且还产生了强大的HIV-1特异性CD4+T细胞反应。最近来自小鼠模型的数据表明，病毒特异性白介素21(IL21)分泌的CD4+T细胞反应对于支持病毒特异性CD8+T细胞和B细胞免疫至关重要。因此，在这项建议中，我们的目标是确定HIV-1特异性IL21+CD4+T细胞反应在HIV-1感染控制中的作用，以确定这些反应的诱导是否应该成为预防和治疗性疫苗的关键组成部分。

DESCRIPTION (provided by applicant): An estimate 6,800 new HIV-1 infections daily dramatically underscores the desperate need for the development of an HIV-1 vaccine. Despite significant advances in our understanding of both the humoral and cellular immune response in HIV-1 infection, the correlates of protection have still not been defined. The recent failure of the Merck vaccine trial and the unexpected modest success of the RV144 HIV vaccine trial using ALVAC-HIV (vCP1521) in a prime boost combination with AIDSVAX B/E, have challenged our notion of what constitutes a protective vaccine. Strikingly, the vaccine induced not only strong antibody responses, but also a robust HIV-1-specific CD4+ T cell response. Approaches to induce HIV-1-specific CD4+ T cell responses have been met with skepticism thus far as these attempts may expand the pool of HIV-1 specific CD4+ T cells targets. However, compelling studies in the lymphochoriomeningitis virus (LCMV) mouse model suggest that virus-specific Interleukin-21 (IL21) secreting CD4+ T cell responses are a critical key factor to establish effective and long-lived virus-specific immunity. Mice lacking IL21 or IL21 receptor (IL21R) were more susceptible to chronic LCMV infection. IL21+CD4+ T cell responses have been shown to enhance cytotoxicity of virus-specific CD8+ T cells and direct antibody class switching and activation of B cells. Thus, IL21+CD4+ T cell responses play a central role in the coordination of virus-specific immunity. Surprisingly little is known about the role of IL21+ CD4+ T cells in human viral infections. Our preliminary data suggest that robust HIV-1- specific IL21+CD4+ T cell responses exist in HIV-1 elite controllers with a preferential targeting of epitopes within the Gag protein. In contrast, in subjects with chronic-progressive HIV-1 infection virtually no IL21+CD4+ T cell responses are detectable. Moreover, we have evidence that IL21 signals can transform non-controlling CD8+ T cell responses into CD8+ T cell responses with strong inhibitory activity. Thus, our preliminary data suggest that IL21+CD4+ T cell responses might be a critical factor for the generation of an effective CD8+ T cell or B cell based vaccine. Specifically we propose to: 1) Determine the presence and specificity of HIV-1-specific IL21+CD4+ T cells as well as their role in the control of viral replication. 2) Determine whether early antiretroviral treatment in primary HIV-1 infection preserves these particular responses. 3.) Assess how HIV-1-specific IL21+CD4+ T responses modulate HIV-1-specific CD8+ T cells and enhance their capacity to inhibit viral replication. 4.) Investigate whether therapeutic CD4-targeted vaccination can induce such responses and finally 5.) assess how IL21+CD4+ T cells modulate HIV-1-specific B cell functions. The underlying hypotheses of this proposal are that HIV-1-specific IL21+ CD4+ T cells have a key function in the control of viral replication by modulating HIV-1-specific B cell function and increasing the inhibitory activity of HIV-1-specific CD8+ T cells. The induction and propagation of these responses in a prophylactic or therapeutic vaccine will be essential for long-lived effective virus-specific immunity. PUBLIC HEALTH RELEVANCE: With 33 million HIV-1 infected individuals world-wide an HIV-1 vaccine is urgently needed. The recent failure of the Merck vaccine trial and the unexpected modest success of a vaccine consisting of a combination of two vaccine candidates (ALVAC/AIDSVAX; "Thai trial") drastically demonstrate our poor understanding how to develop an effective vaccine. Strikingly, the used vaccine not only induced antibodies, but also a robust HIV-1-specific CD4+ T cell response. Recent data from the mouse model suggest that virus-specific Interleukin-21 (IL21)-secreting CD4+ T cell responses are critical to support virus-specific CD8+ T cell and B cell immunity. Thus in this proposal we aim to define the role of HIV-1-specific IL21+CD4+ T cell responses in the control of HIV-1 infection to determine whether the induction of these responses should be a key component of a prophylactic and therapeutic vaccine.